| Literature DB >> 33681815 |
Ahmad S Alotaibi1, Musa Yilmaz1, Rashmi Kanagal-Shamanna2, Sanam Loghavi2, Tapan M Kadia1, Courtney D DiNardo1, Gautam Borthakur1, Marina Konopleva1, Sherry A Pierce1, Sa A Wang2, Guilin Tang2, Veronica Guerra1, Bachar Samra1, Naveen Pemmaraju1, Elias Jabbour1, Nicholas J Short1, Ghayas C Issa1, Maro Ohanian1, Guillermo Garcia-Manero1, Kapil N Bhalla1, Keyur P Patel2, Koichi Takahashi1, Michael Andreeff1, Jorge E Cortes3, Hagop M Kantarjian1, Farhad Ravandi1, Naval Daver4.
Abstract
Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1, and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS mutated patients, pretreatment cohort level variant allelic frequencies for RAS were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i.Entities:
Keywords: FLT3 mutated AML; FLT3-inhibitor resistance; Type I; Type II; emergent mutations
Mesh：
Substances：
Year: 2020 PMID： 33681815 PMCID： PMC7935111 DOI： 10.1158/2643-3230.BCD-20-0143
Source DB: PubMed Journal: Blood Cancer Discov ISSN： 2643-3230